This application addresses broad Challenge Area 03: Biomarker Discovery and Validation and specific Challenge Topic, 03-MH-101 "Biomarkers in mental disorders." The proposal is designed to develop a biomarker and physiological endophenotype for schizoaffective disorder (SAD). Schizoaffective disorder, much like autism, has gone from a rarity - Kasanin described but 9 cases in his original 1933 report - to a psychotic disorder more common than schizophrenia (SZ) - the Mental Health Corp of Denver, the primary provider of mental health services to the Denver- Boulder metropolitan region - has 813 patients with a SAD diagnosis, but only 748 with a SZ diagnosis as of this date. SAD is usually grouped with schizophrenia (SZ) in research studies, but if it is in fact an independent entity as our preliminary data suggests, this may be an error. We believe we may be able to use MEG recordings to establish an objective and reliable biomarker, or endophenotype, for SAD, and to differentiate it from SZ. If SAD has an independent endophenotypic grouping, as we suspect may be the case, combining SAD and SZ patients in the same cohort can only confuse and introduce error into studies of pathophysiology, treatment, and outcome of these serious psychotic disorders. Whole head MEG recordings of subjects listening to bursts of 1Kz tones amplitude modulated at 40Hz, demonstrate a neocortical gamma band response termed the Steady State Response (SSR), whose amplitude and phase control is thought to estimate functional status of GABAergic interneuronal activity regulating firing patterns of layer 3 pyramidal cells in auditory cortex of Heschl's gyrus. Schizophrenic (SZ) patients demonstrate a significant functional impairment in this gamma band SSR response in both left and right auditory cortex, interpreted as impaired interneuronal inhibitory mechanisms. We have recently however recorded a small cohort of patients with a diagnosis of SAD who exhibit functional impairments in the left hemisphere similar to that found in SZ, but demonstrate preservation of the MEG gamma band SSR response in the right hemisphere, with amplitude and phase control no different from normal controls (NC). We hypothesize that this preservation of right hemisphere auditory cortex functional activity may relate to phenotypic characteristics that have been described in SAD subjects, who often have better premorbid function, more emotional responsivity (auditory emotional prosody), and more favorable outcome compared to SZ subjects. Ultimately an effective biomarker should be capable of distinguishing individual cases, not just group differences. e believe that 248 channel whole head MEG in combination with the methods of source space projection and phase and amplitude analysis using wavelet based complex demodulation may be able to provide the functional and structural accuracy necessary to permit establishment of group normal values that will prove useful in the diagnosis of individual patients. This study is designed to use whole head MEG recordings to rigorously test 3 hypotheses: 1) SAD subjects will demonstrate relative preservation of phase control of right hemisphere gamma band SSR, not significantly different from that in NC, whereas SZ subjects will demonstrate significantly reduced right hemisphere SSR phase control compared to NC and SAD, 2) R hemisphere gamma band SSR response will index performance on a formal test of auditory emotional prosody which will be similar to that in NC and significantly better than in subjects with SZ, 3) SSR gamma band amplitude and phase control will be significantly correlated with intra- cortical GABA concentration in auditory cortex as estimated by magnetic resonance spectroscopy (MRS). The outcome of the proposed research will facilitate placement of SAD as an independent entity within the SZ- bipolar spectrum, and result in a behavioral and MEG based physiological endophenotype to separate SAD from SZ. Objective biomarkers identifying and individuating the major mental illness will greatly facilitate optimal design of future studies relating to pathophysiology, diagnosis, treatment response, and outcome. PUBLIC HEALTH NARRATIVE: The major mental disorders including schizophrenia represent one of the major components of health care costs in the United States. Our inabilities to accurately diagnose these disorders based on objective and reliable physiological biomarkers that separate one from another is a major limitation to finding underlying causes and develop rational treatments. This proposal is designed to identify and isolate a physiological biomarker for schizoaffective disorder, a disorder confused with schizophrenia, but which may represent a separate independent disorder. Separation of schizoaffective disorder from schizophrenia will greatly facilitate targeted research in pathophysiology and more rational studies of treatment of each.